Ischemia and reperfusion is one of the major mechanisms underlying human disease. Ischemia occurs when the arterial or oxygenated blood supply is interrupted to an organ or tissue. Reperfusion refers to the reestablishment of blood flow after the period of ischemia. Studies in rodents and large animals demonstrate that the complement system is a major mediator of ischemia-reperfusion injury in various tissues including myocardium, central nervous system, intestine and hindlimb. Our recent results identified natural IgM antibody as the initial step in complement-dependent injury. This phase I application proposes two specific aims: (1) determine the feasibility of identification of specific B-1 cell hybridomas that secrete pathogenic IgM; (2) examine the feasibility of identifying peptides that bind to the specific IgM antibodies that initiate injury. Successful completion of phase I will lead to phase II which will test the proof-of-concept that mutant IgM (does not bind complement) and/or peptides that bind IgM will block reperfusion injury in vivo. Reperfusion injury is a documented major mechanism of injury following heart attack or coronary events, stroke and trauma estimated to affect over 13 million patients per year and representing a $ 3.5 billion market. Currently, there are no effective treatments for blocking injury. Development of a specific inhibitor of reperfusion injury at the earliest stage of inflammation would provide an important medical benefit. The identification of an inhibitor/s that act at the induction stage of injury would have broad commercial application given the many types of tissues affected by reperfusion injury. The identification of hybridoma clones, which secrete antibody that initiates injury, or specific inhibitors of endogenous IgM will provide an important basis for development of future therapie.